Aberrant protein processing and tissue deposition is commonly associated with neurodegenerative disease; a common etiology suggests the potential for common therapy. The problem however, is that most neurodegenerative disease results from a complex array of genetic and environmental factors. We recently described an autosomal dominant neurodegenerative disease causing both epilepsy and progressive dementia called familial encephalopathy with neuroserpin inclusion bodies (FENIB). This disorder is caused by point mutations in the gene (PI12 ) encoding a serine protease inhibitor neuroserpin. The mutations are expressed as conformationally unstable neuroserpin molecules that polymerize and aggregate into characteristic inclusions which are identified as Collins bodies. We hypothesize that FENIB is an endoplasmic reticulum storage (ERSD) disorder. The Specific Aims designed to test this hypothesis are: 1) to determine if the chemical composition of the neuroserpin isolated from Collins bodies is consistent with an ER-retained secretory protein, and 2) to decipher the cellular processing of nascent wild-type and mutant neuroserpins in transfected AtT20 cells. We propose that mutant neuroserpins are retained by the ER, that ER retention is exacerbated by stress, and that ER retention disrupts cellular homeostasis. FENIB shares a common molecular pathophysiology with other mutated serpins, i.e., the capacity to undergo a profound conformational change with resultant polymerization and tissue deposition. We hypothesize that this conformational mobility explains the phenotypic variability seen among the FENIB affected individuals. Therefore, another goal is to test the relationship between FENIB and ERSD by correlating the stability of each mutant, as predicted by molecular modeling, to its cellular processing and relating this information to the clinical and neuropathological effects each mutation produces. The findings from our study should clarify how protein polymerization and aggregation with subsequent ER retention initiates pathogenesis, and should thereby suggest therapeutic interventions that could prevent, ameliorate, or even reverse the progression of this and other protein conformational diseases.